The therapeutic problem we address is how to inhibit the development and progression of IPMN (intraductal papillary mucinous neoplasm), PanIN (Pancreatic Intraepithelial Neoplasia) and PDA (pancreatic ductal adenocarcinoma). The biological problem is to identify key signaling pathways that initiate and propagate IPMN, PanIN and PDA. A central debate in the field is whether PDA initiates in pancreatic progenitor cells or with dedifferentiation of parenchymal acinar cells to progenitor-like ductal cells, in a process termed acinar to ductal metaplasia (ADM). The function of the transcription factor Master Regulators (MRs) of acinar cell identity is critical to this process but post-translational regulaton of their activity through receptor tyrosine kinase (RTK) and G protein coupled receptor (GPCR) signaling is completely unexplored. Regulators of G protein signaling (RGS) proteins integrate multiple intracellular signals from RTKs and GPCRs to feedback regulate Gi and Gq protein signaling. We have developed a GFP reporter (Rgs16:GFP) that allows us to monitor neoplasia and tumor formation from early stages in in vivo mouse models of IPMN, PanIN and PDA. Combining the Rgs16:GFP reporter with mouse models for IPMN, PanIN and PDA is providing insights into development of these tumors and a novel and rapid in vivo screen for inhibitors of this process. We discovered RGS genes that suppress progression of IPMN to invasive carcinoma. Based on preliminary analyses using these models, we find that IPMN and PanIN initiate in discrete ductal progenitor cells in response to stress in the acinar or endocrine compartments of the pancreas. This interpretation challenges the currently favored paradigm that PDA initiates with cells that underwent ADM whereas we propose that chronic ADM stimulates proliferation of pre-existing progenitor cells in ducts. We find that the RTK Axl is expressed in pancreatic ducts and is highly expressed with Rgs16:GFP in PDA progenitor cells in primary culture. Our hypothesis is that the Axl-ligand Gas6 expressed in stroma evokes Axl signaling in epithelial progenitor cells and contributes to activation of KrasG12D, post-translational control of MR levels and/or activity, PDA initiation and progression. In our preliminary in vivo screens of new therapeutics to inhibit PDA progression, we determined that warfarin, which blocks Gas6 induced activation of Axl, combined with the standard of care Gemcitabine and Abraxane (GA), significantly reduced PDA progression. The Specific Aims of this proposal are 1) Identify optimal drug combinations, including inhibitors of Axl signaling, to inhibit PDA. 2) Identify early markers of IPMN, PanIN and PDA in plasma. 3) Determine Gas6-Axl function in PDA. The proposed project, if successful, will have a major impact on cancer by i) identifying early blood markers of PDA, and perhaps other epithelial cancers, ii) introducing a novel, general and rapid in vivo screening technique to find novel drug combinations that inhibit PDA progression, iii) providing novel genetic tools to determine if PDA initiates in progenitor cells in the pancreatic duct, Iv) identify previously unknown regulatory mechanisms of the MR transcription factors.